Purpose: 235 premenopausal women at increased risk for breast cancer have been enrolled in a multicentric, randomized, double blind, placebo-controlled phase IIb trial to investigate the effect of low dose tamoxifen, fenretinide (a vitamin A derivative), their combination or placebo on different surrogate endpoint biomarkers, including IGF-I, mammographic density (primary endpoints) and circulating sex steroid hormones. The present analysis refers to baseline correlation between biomarkers. Patients and methods: From October 1998 to April 2002 a total of 181 DCIS patients and 54 at-risk women according to the Gail model have been randomized in two study centres. Participants were treated for two years and followed for an additional year after treatment completion. Fasting blood samples and mammography were taken at baseline and every 12 months, within the same phase of the menstrual cycle. Samples were stored at -80°C till central assay. Results: Mean (+SD) age at randomization was 46.2+4.2 years. Mean (+SD) baseline FSH, prolactin, SHBG, LH, DHEAS, progesterone, 17betaestradiol levels were 15.9+15.4 mIU/ml, 13.2+6.0 ng/ml, 77.7+34.5 nmol/l, 14.2+14.1 mIU/ml, 1199+714 ng/ml, 0.95+1.77 ng/ml and 149.8+110.5 pg/ml in the follicular phase, and 17.6+26.9 mIU/ml, 16.1+18.7 ng/ml, 84.8+41.7 nmol/l, 16.2+19.7 mIU/ml, 1189+687 ng/ml, 5.98+5.99 ng/ml and 169.5+114.8 pg/ml in the lutheal phase, respectively. Mean baseline retinol level was 559+121 ng/ml. After adjustment for disease status (DCIS versus Gail), age at randomization, phase of the menstrual cycle, center and mammographic percent density, women with prior DCIS had higher levels of FSH (p=0.003) and LH (p=0.001) level and lower SHBG (p <.0001) and E2 levels (p=0.065) compared to the Gail group. Mean (+SD) baseline mammographic density was 39.5+18.6% without differences between DCIS and Gail participants. Also, mean IGF-I levels were 9% higher in women with prior DCIS than unaffected women (p=0.068). As expected, there was an inverse correlation between age and mammographic density, the latter decreasing by 0.7% points per year over the age range 30 to 57 years as well as an inverse correlation between age and IGF-I, the latter decreasing by 2% per year. A direct correlation has been observed between mammographic density and SHBG (p=0.006) and an inverse correlation has been observed between retinol levels and mammographic density (p=0.051). Conclusions: Premenopausal women with prior DCIS show different levels of endogenous hormones relative to healthy women at increased risk for breast cancer. In these subjects mammographic density is directly influenced by hormone availability and is inversely correlated with endogenous vitamin A levels. The hormonal effects during treatment will be presented at the conference.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]